Addition of Capecitabine to T-DM1 in Previously Treated Patients With HER2-Positive Metastatic Breast Cancer

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In the phase I/II TRAXHER2 trial reported in JAMA Oncology, Cortés et al found that the combination of capecitabine and ado-trastuzumab emtansine (T-DM1) did not improve overall response rate vs T-DM1 alone in previously treated patients with HER2-positive metastatic breast cancer.

Study Details

In the phase I portion of the trial, the capecitabine dosage to be used in combination with T-DM1 in the phase II portion was determined in 11 patients with metastatic breast cancer and 6 with locally advanced or metastatic gastric cancer. The capecitabine maximum tolerated dose was identified as 700 mg/m2.

In the open-label international phase II portion, 161 patients with previously treated metastatic breast cancer were randomly assigned between October 2014 and April 2016 to receive capecitabine at 700 mg/m2  twice daily on days 1 to 14 of 3-week cycles plus T-DM1 at 3.6 mg/kg every 3 weeks or T-DM1 alone until disease progression or unacceptable toxicity. Random assignment was stratified by prior number of treatments. The primary outcome measure was investigator-assessed overall response rate using Response Evaluation Criteria in Solid Tumors version 1.1.

Response Rates


  • No significant difference in objective response rate was observed in patients treated with T-DM1 plus capecitabine vs T-DM1 alone.
  • Objective response rates were 44% vs 36%.

Objective response was observed in 36 (44%) of 81 patients in the T-DM1/capecitabine group vs 29 (36%) of 80 in the T-DM1–alone group (difference = 8.2%, 90% confidence interval [CI] = −4.5 to 20.9, P = .34). Complete response was observed in two patients in each group. Median duration of response was 11.3 vs 12.2 months.

Median progression-free survival was 10.2 months (90% CI = 7.9–12.6 months) in the combination group vs 9.8 months (90% CI = 7.5–13.1 months) in the T-DM1–alone group (stratified hazard ratio [HR] = 0.92, 90% CI = 0.67–1.25). Median overall survival was not estimable (90% CI = not estimable–not estimable) vs 24.7 months (90% CI = 24.3 months–not estimable; stratified HR = 0.87, 90% CI= 0.51–1.48).

Adverse Events

Grade 3 or 4 adverse events occurred in 44% of patients in the combination group vs 41% in the T-DM1–alone group, with the most common being thrombocytopenia (10% in the combination group vs 4% in the T-DM1–alone group), increased aspartate transaminase (5% vs 6%), and increased γ-glutamyltransferase (5% vs 6%). Grade 4 adverse events consisted of thrombocytopenia, brain edema, and pulmonary embolism in one patient each in the combination group, and thrombocytopenia, hepatocellular injury, and bacterial sepsis in one patient each in the T-DM1–alone group.

Adverse events led to discontinuation of treatment in 28% vs 15% of patients, with the most common cause being thrombocytopenia in both groups (6% vs 4%). No adverse events led to death.

The investigators concluded, “Adding capecitabine to T-DM1 did not statistically increase overall response rate associated with T-DM1 in patients with previously treated [HER2]-positive metastatic breast cancer. The combination group reported more adverse events, but with no unexpected toxic effects."

Karen Gelmon, MD, of BC Cancer and the Division of Medical Oncology, University of British Columbia, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was funded by F. Hoffmann-La Roche, Ltd. For full disclosures of the study authors, visit